Dosage form comprising drug and maltodextrin

ABSTRACT

A dosage form is disclosed comprising a drug and a maltodextrin polymer for administering to a patient a drug in need of therapy.

DESCRIPTION OF TECHNICAL FIELD

This invention pertains to an improvement in a dosage form. The dosageform comprises a wall that surrounds a compartment comprising a drug,wherein the improvement comprises a maltodextrin in the compartment thatcooperated with the dosage form for delivering the drug from thecompartment, while concomitantly permitting the drug to substantiallymaintain both its chemical integrity and therapeutic activity.

DESCRIPTION OF BACKGROUND ART

Dosage forms for delivering a drug to a biological environment of useare known to the prior art in U.S. Pat. Nos. 3,845,770 and 3,916,899,issued to the patentees Felix Theeuwes and Takeru Higuchi. The dosageforms disclosed in these patents comprise a wall that surrounds aninternal compartment containing the drug. The wall is permeable to thepassage of an external fluid and it is substantially impermeable to thepassage of drug. There is at lease one passageway through the wall fordelivering the drug from the dosage form. These dosage forms release thedrug by fluid being imbibed through the wall into the compartment at arate determined by the permeability of the wall and the osmotic pressuregradient across the wall to produce an aqueous solution containing drugthat is dispensed through the passageway from the dosage form. Thesedosage forms are extraordinarily effective for delivering an agent thatis soluble in fluid imbibed into the dosage form that exhibits andosmotic pressure gradient across the wall against an external fluid.

A pioneer advancement in dosage form invention was presented to the drugdelivery arts by Richard Cortese and Felix Theeuwes in U.S. Pat. No.4,327,725. The invention disclosed and claimed in this patent pertainedto enhancing the delivery kinetics of the dosage form for deliveringdrugs with various degrees of solubility in aqueous fluids that aredifficult to deliver, by manufacturing the dosage form comprising ahydrogel. The hydrogel in the presence of fluid imbibed into the dosageform, swells and moves from a rested state to an expanded state. Theforce generated by the expansion of the hydrogel is applied against thedrug thereby pushing the beneficial drug through the passageway from thedosage form.

The dosage forms provided by the prior art operate successfully fortheir use, and they can deliver numerous drugs. Now, it has been foundthat some hydrogels used in these dosage forms often exhibit an unwantedeffect on the drug, that causes it to lose its chemical integrity andtherapeutic activity. That is, the drug may decompose and consequentlythe intact drug is not available for delivery from the dosage form.

In light of the above presentation, it will be appreciated by thoseversed in the dispensing art to which this invention pertains, that apressing need exists for a rate controlled dosage form that can delivera drug intact to a patient in need of therapy. It will be appreciatedfurther by those versed in the delivery arts, that if a dosage form isprovided comprising a hydrogel that can deliver a drugsubstantially-free of the unwanted effects of the prior art, such adosage form would have a positive value and it also would represent bothan improvement and an advancement in the dispensing arts.

DISCLOSURE OF OBJECTS OF THE INVENTION

Accordingly, it is an immediate object of this invention to provide adosage form for the controlled delivery of a drug, by providing a dosageform that represents a further improvement and advancement in thedelivery arts.

Another object of this invention is to provide a novel and useful dosageform manufactured as an osmotic delivery device, the use of which dosageform requires intervention only for initiation of its use for producinga therapeutic result.

Another object of this invention is to provide a dosage form that candeliver a substantial amount of a drug rate controlled by the dosageform throughout the day, with once, and sometimes twice daily, dosing bythe dosage form.

Another object of this invention is to provide a dosage form comprisinga compartment comprising a drug and an expandable hydrophilicmaltodextrin that is substantially-free of exhibiting an unwanted effecton the drug.

Another object of the present invention is to provide a dosage form fordelivering a drug wherein the drug and a maltodextrin are in the dosageform, with the maltodextrin substantially-free from exerting an adverseor deteriorating effect on the drug.

Another object of this invention is to provide a dosage form comprisinga pharmaceutically acceptable maltodextrin that is chemically inert,safe for administering to a warm-blooded animal, and imparts stabilityto a drug in a dosage form.

Another object of the invention is to provide a dosage form having acompartment comprising a drug that is insoluble to very soluble in anaqueous fluid, and an expandable maltodextrin driving member, whichmaltodextrin operates by expanding to diminish the space occupied by thedrug, thereby delivering the drug from the dosage form at a controlledrate over time.

Another object of the invention is to provide an osmotic dosage formhaving a compartment housing a layer of a composition comprising a drug,and an adjacent layer of a composition comprising an expandablemaltodextrin, which latter layer continuously increases its volume whilecorrespondingly decreasing the volume initially occupied by the drugcomposition during the operation of the dosage form.

Another object of the present invention is to provide a dosage formmanufactured as an osmotic dosage form that can deliver a drug whilesimultaneously substantially reducing and/or substantially eliminatingthe unwanted influences of the gastrointestinal tract environment ofuse.

Another object of the present invention is to provide a dosage formdesigned and manufactured as an osmotic device containing a drug and amaltodextrin, which drug is delivered in a dose amount for producing thedesired therapeutic effect, and which device delivers substantially afull complement of the drug, thereby avoiding the need for a drugoverage in the dosage form.

Another object of the invention is to provide a dosage form thatprovides instant drug therapy and prolonged drug therapy using amaltodextrin.

Other objects, features and advantages of the invention will be moreapparent to those versed in the dispensing arts from the followingdetailed specification, taken in conjunction with the drawings and theaccompanying claims.

BRIEF DISCLOSURE OF THE DRAWING FIGURES

In the drawing figures, which are not drawn to scale, but are set forthto illustrate various embodiments of the invention, the drawing figuresare as follows:

Drawing FIG. 1 is a view of a dosage form, designed, shaped and adaptedfor administering orally a drug in the gastrointestinal of a human inneed of therapy;

Drawing FIG. 2 is an opened view of the dosage form of drawing FIG. 1for illustrating the internal structure and ingredients of a dosageform;

Drawing FIG. 3 is an opened view of the dosage form of drawing FIG. 1for illustrating the internal structure comprising a first drugcomposition and a second maltodextrin composition;

Drawing FIG. 4 is an opened view of the dosage form of drawing FIG. 1,which drawing FIG. 4 depicts the structure of the dosage form comprisinga first drug composition, a second maltodextrin composition, and aninstant drug released on the outside of the dosage form;

Drawing FIG. 5 is an opened view of the dosage form of drawing FIG. 1,which drawing FIG. 5 depicts a multiporous releasing member forreleasing drug from the dosage form;

Drawing FIG. 6 is a graph that illustrates the amount of drug releaseper hour from a dosage form; and

Drawing FIG. 7 is a graph that illustrates the amount of drug release ina cumulative amount over a prolonged time of 24 hours.

In the drawing figures, and in the specification, like parts in relateddrawing figures are identified by like numbers. The terms appearingearlier in the specification and in the description of the drawingfigures, as well as embodiments thereof, are further described elsewherein the specification.

DETAILED DISCLOSURE OF THE DRAWING FIGURES

Turning now to the drawing figures in detail, which drawing figures arean example of the dosage form provided by this invention, and whichexample is not to be construed as limiting, one example of the dosageform is illustrated in drawing FIG. 1, and designed by the numeral 10.In drawing FIG. 1, dosage form 10 comprises a body member 11 comprisingwall 12, which wall surrounds an enclosed internal compartment, not seenin drawing FIG. 1. Dosage form 10 comprises at least one exit means 13in wall 12, which exit means connects the exterior environment of usewith the interior of dosage form 10.

In drawing FIG. 2, dosage form 10 is manufactured as an osmotic device,and it is seen in opened view. In drawing FIG. 2, dosage form 10comprises body 11, a wall 12, which wall surrounds and defines aninternal compartment 14. Wall 12 comprises at least one exit means 13that connects compartment 14 with the exterior of dosage form 10. Dosageform 10 can comprise more than one exit means, as presented later in thespecification.

Wall 12 of dosage form 10, comprises totally, or in at least a part, acomposition that is permeable to the passage of an exterior fluidpresent in the environment of use. Wall 12 is substantially impermeableto the passage of a drug and to other optional ingredients that may bepresent in compartment 14. The semipermeable wall 12 is substantiallyinert, that is, wall 12 maintains its physical and chemical integrityduring the dispensing of a therapeutic drug form dosage from dosage form10. Wall 12, in a presently preferred embodiment is formed totally or inat least a part of a member selected from the group consisting of acellulose ether, cellulose ester, and cellulose ester-ether. Thesecellulosic polymers have a degree of substitution, D.S., on theanhydroglucose unit, from greater than 0 up to 3 inclusive. By degree ofsubstitution is meant the average number of hydroxyl groups originallypresent on the anhydroglucose unit comprising the cellulose polymer thatare replaced by a substituting group. Representative materials include amember selected from the group consisting of cellulose acylate,cellulose diacylate, cellulose triacylate, cellulose acetate, cellulosediacetate, cellulose triacetate, mono, di and tricellulose, alkanylates,mono, di and tricellulose aroylates, and the like. Exemplary polymersinclude cellulose acetate having a D.S. up to 1 and an acetyl content upto 21%; cellulose acetate having an acetyl content of 32 to 39.8%;cellulose acetate having a D.S. of 1 to 2 and an acetyl content of 21 to35%; cellulose acetate having a D.S. of 2 to 3 and an acetyl content of35 to 44.8%, and the like. More specific cellulosic polymers includecellulose propionate having a D.S. 1.8 and a propyl content of 39.2 to45% and a hydroxyl content of 2.8 to 5.4%; cellulose acetate butyratehaving a D.S. of 1.8, an acetyl content of 13 to 15% and a butyrylcontent of 34 to 39%; cellulose acetate butyrate having an acetylcontent of 2 to 29%, a butyryl content of 17 to 53% and a hydroxylcontent of 0.5 to 4.7%; cellulose triacylates having a D.S. of 2.9 to 3such as cellulose triacetate, cellulose trivalerate, cellulosetrilaurate, cellulose tripalmitate, cellulose trisuccinate, andcellulose trioctanoate; cellulose diacylates having a D.S. of 2.2 to2.6% such as cellulose disuccinate, cellulose dipalmitate, cellulosedioctanoate, cellulose dipentanoate, co-esters of cellulose such ascellulose acetate butyrate and cellulose acetate propionate, and thelike.

Additional semipermeable polymers include acetaldehyde dimethylcellulose acetate, cellulose acetate ethyl carbamate, cellulose acetatemethyl carbamate, cellulose acetate dimethyl aminoacetate, semipermeablepolyamides; semipermeable polyurethanes; semipermeable sulfonatedpolystyrenes; semipermeable cross-linked selectively permeable polymersformed by the coprecipitation of a polyanion and a polycation asdisclosed in U.S. Pat. Nos. 3,173,876; 3,276,586; 3,541,005; 3,541,006;and 3,546,142; semipermeable polymers as disclosed by Loeb andSourirajan in U.S. Pat. No. 3,133,132; semipermeable lightlycross-linked polystyrene derivatives; semipermeable cross-linkedpoly(sodium styrene sulfonate); and semipermeable cross-linkedpoly(vinylbenzyltrimethyl ammonium chloride). The polymers are known tothe art in U.S. Pat. Nos. 3,845,770; 3,916,899; and 4,160,020; and inHandbook of CommonPolymers by Scott, J. R. and Roff, W. J., 1971,published by CRC Press, Cleveland, Ohio.

In another embodiment, wall 12 comprises additionally from 0 weightpercent, "wt %," to 30 weight percent of a member selected from thegroup consisting of a cellulose ether selected from the group consistingof a hydroxypropylcellulose and a hydroxypropylmethylcellulose, and from0 weight percent to 30 weight percent of a polyethylene glycol. Thetotal weight of all components comprising wall 12 is equal to 100 weightpercent.

Internal compartment 14 comprises a drug 15, represented by dots, whichdrug is present in a therapeutically effective amount comprising 10nanogram to 650 mg for producing a therapeutic effect. Compartment 14also comprises from 0 weight percent to 35 weight percent of ahydroxypropylmethylcellulose, identified by dashes 16 comprising a 9,000to 300,000 molecular weight; from 0 weight percent to 75 weight percentof hydroxypropylcellulose represented by vertical lines 17 andcomprising 10,000 to 100,000 molecular weight, from 0 weight percent to75 weight percent of a polyvinyl pyrrolidone represented by slantedlines 18 comprising a 20,000 to 275,000 molecular weight; from 5 weightpercent to 75 weight percent of a maltodextrin polymer compositioncomprising the formula (C₆ H₁₂ O₅)_(n) H₂ O wherein n is 3 to 6,140 andthe maltodextrin polymer comprises a 500 to 1,000,000 number averagemolecular weight represented by hexagon 19, and from 0 to 3 weightpercent of a lubricant such as magnesium stearate, or stearic acid; withthe total weight of all ingredients equal to 100 weight percent.

Drawing FIG. 3, seen in opened view, depicts a dosage form 10 comprisingin compartment 14 a first composition 20 and a second composition 21.The first composition 20 and the second composition 21 initially are inlaminar arrangement and they cooperate with each other and with dosageform 10 for effectively delivering drug 15 from dosage form 10. Firstcomposition 20 also comprises from 0 weight percent to 25 weight percentof a hydroxypropylmethylcellulose 16 comprising a 9,000 to 300,000average molecular weight; from 0 weight percent to a 50 weight percentof a hydroxypropylcellulose 17 comprising a 10,000 to 300,000 molecularweight; from 0 weight percent to 50 weight percent of a polyvinylpyrrolidone 18 comprising a 20,000 to 275,000 molecular weight; from 5to 95 l wt % of maltodextrin polymer 19 of the formula (C₆ H₁₂ O₅)_(n)H₂ O wherein n is 3 to 61,400 and the maltodextrin polymer comprises a500 to 10,000,000 number average molecular weight. The maltodextrin cancomprise a broad range of average degree of polymerization and molecularweight such as a degree of polymerization, "DP", of 3.1 and a molecularweight, "mol. wt", of 500; a DP of 4.5 and a mol. wt of 720; a DP of 5.6and a mol. wt of 900; a maltodextrin polymer having a DP of 7.4 and amol. wt of 1200; a DP of 11.1 and a mol. wt of 1800; a DP of 22.1 and amol. wt of 3600; and the like. The maltodextrin can be formulated intofirst composition 20 by manufacturing processes including wet, dry orfluidizing processes. The maltodextrins are pharmaceutically acceptable,they are compatible with other ingredients in second composition 21,they are free-flowing powders in their dry state and on imbibing anaqueous fluid they form an expanding, osmotic plastic paste at 75 to100% relative humidity. The maltodextrin polymers are commerciallyavailable from the Grain Processing Corporation of Muscatine, Iowa.First composition 20 may optionally comprise from 0 wt % to 3 wt % of alubricant such as a member selected from the group consisting of stearicacid, magnesium stearate, zinc stearate, zinc oleate, zinc palmitate,calcium stearate, micronized polyethylene glycol, finely divided teflonand hydrogenated castor oil; and from 0 to 3 wt % of a surfactantselected from the group consisting of nonionic, anionic, cationic,amphoteric surfactants, micelles surfactants, olefin surfactants,quaternary surfactants, and the like, with the total amount of allcomponents in the first composition equal to 100 wt %.

Second composition 21 comprises from 0 to 40 weight percent of anosmotically effective compound, which are also known as osmoticallyeffective solutes and osmagents, and they are represented in drawingFIG. 3 by half-circles 22. The osmotic solutes 22 are homogeneously orheterogeneously blended with other second composition 21 formingingredients for imbibing an external fluid through wall 12 intocomposition 21. Osmotically effective solutes used for the purpose ofthis invention comprise a member selected from the group consisting ofmagnesium sulfate, magnesium chloride, potassium sulfate, sodiumsulfate, lithium sulfate, mannitol, urea, inositol, magnesium succinate,sodium chloride, potassium chloride, raffinose, sucrose, glucose,lactose, sorbitol and the like. Osmotic solutes and procedures formeasuring their osmotic pressure using a Model 320B, Vapor PressureOsmometer, manufactured by Hewlett-Packard Co., Avondale, PA., aredisclosed by Wong et al in U.S. Pat. No. 4,765,989.

Second composition 21 comprises from 5 weight percent to 95 weightpercent of a hydrogel identified by V 23. The hydrophilic compositionsuitable for forming second composition 21 are swellable, hydrophilicpolymers. The presently preferred materials useful for forming secondcomposition 21 comprise hydrogels that exhibit the ability to swell andexpand in the presence of water and retain a significant fraction ofwater within the hydrogel structure. The hydrogels can benoncross-linked, or they can be lightly crossed linked. The polymerhydrogels swell or expand to a very high degree in the presence ofaqueous type fluids, usually exhibiting a 2 to 60 volume increase. Thisexpansion against first composition 20 results in the drug beingdelivered through exit passageway 13. Hydrophilic polymeric compositionsuseful for the present purpose include poly(hydroxyalkyl methacrylate);poly(N-vinyl-2-pyrrolidone); anionic hydrogels; cationic hydrogels;polyelectrolyte hydrogel complexes; poly(-vinyl alcohol) cross-linkedwith glyoxal, formaldehyde or glutaraldehyde; copolymers produced byforming a dispersion of finely divided copolymer of maleic anhydridewith styrene, ethylene, propylene, butylene or isobutylene; polymericN-vinyl lactams; carboxypolymers available as Carbopol® polymer;Cyanamer® polyacrylamides cross-linked with inden-maleic anhydride;Good-Rite® polyacrylic acid; Aqua Keeps® acrylate polymer; diestercross-linked polyglucan; polyethylene oxide; copolymers of N-vinyllactam with N-vinyl piperidione; Water Lock® starch-graft-poly(iodineacylate-co-acrylamide); sodium carboxymethylcellulose; and the like. Thedegree of expansion is calculated by subtracting the weight of the dryhydrogel from the weight of the aqueous swollen hydrogel divided by theweight of the dry hydrogel times 100. The hydrogel polymers aredisclosed in U.S. Pat. No. 4,327,725 issued to Cortese and Theeuwes, andin U.S. Pat. No. 4,612,008 issued to Wong, Barclay, Deters and Theeuwes.Second composition 21 comprises from 0 to 25 wt % of ahydroxypropylcellulose identified by triangle 24, and from 0 to 35 wt %hydroxypropylmethylcellulose identified by squares 25. Secondcomposition 21 optionally comprises from 0 wt % to 3 wt % of a coloringagent such as ferric oxide and optionally from 0 to 3 wt % of allingredients present in second composition 21 is equal to 100 wt %.

Dosage form 10, as seen in drawing FIG. 4, is manufactured as an osmoticdevice comprising an external drug coat 26 on the exterior orsemipermeable wall 12. Coat 26 is a composition comprising 1 mg to 100mg of drug 15, represented by the dots, and an aqueous soluble carriersuch as a low molecular weight, 5,000 to 200,000 grams per molehydroxypropylcellulose, or a low molecular weight, 9,000 to 22,000 gramsper mole hydroxypropylmethylcellulose. The coat optionally contains aplasticizer such as polyethylene glycol. Drug coat 26 provides instanttherapy as coat 26 dissolves or undergoes dissolution or disintegrationin the presence of aqueous and biological fluids and concurrentlytherewith delivers a drug to a drug receptor. Drug coat 26 providesimmediate drug delivery, thereby essentially overcoming the timerequired for a drug to be delivered from internal compartment 14. Astart-up time is needed for imbibing fluid through wall 12 for dosageform 10 to osmotically and hydrodynamically pump drug from dosage form10 through exit means 13.

Drawing FIG. 5 depicts, in opened section, another drug delivery deviceprovided by the invention. In drawing FIG. 5, exit means 13 comprises amicroporous inlay that spreads the drug as it is osmotically releasedfrom the dosage form 10. The expression, "exit means" 13, as usedherein, comprises means and methods suitable for the metered release ofa beneficial drug from compartment 15 of dosage form 10. The means 13includes at lease one passageway, orifice, or the like, through wall forcommunicating with in compartment 14. The expression, at least onepassageway, includes aperture, orifice, bore, pore, porous elementthrough which the drug can be pumped, diffuse, travel or migrate, hollowfiber, capillary tube, porous overlay, porous insert, microporousmember, and the like. The expressions also includes a material thaterodes or is leached from wall 12 in the fluid environment of use toproduce at least one passageway in dosage form 10. Representativematerial suitable for forming at least one passageway, or a multiplicityof passageways, include an erodible poly(glycolic) acid or poly(lactic)acid member in the wall; a gelatinous filament, poly(vinyl alcohol);leachable materials such as fluid removable pore formingpolysaccharides, salts, or oxides, and the like. A passageway or aplurality of passageways can be formed by leaching a material such assorbitol, sucrose, lactose, fructose, or the like, from the wall. Thepassageway can have any shape such as round, triangular, square,elliptical, and the like, for assisting in the metered release of drugfrom dosage form 10. Dosage form 10 can be constructed with one or morepassageways in spaced apart relations on one or more than a singlesurface of a dosage form. Passageways and equipment for forming passagesare disclosed in U.S. Pat. Nos. 3,845,770 and 3,916,899 by Theeuwes andHiguchi; in U.S. Pat. No. 4,063,064 by Saunders et al; and in U.S. Pat.No. 4,088,864 by Theeuwes et al. Passageways formed by leaching toprovide a drug-releasing pore of controlled osmotic release rate aredisclosed in U.S. Pat. No. 4,200,098 by Ayer et al; and in U.S. Pat. No.4,285,987 by Ayer et al.

The expression, "drug 15", as used for the purpose of this inventioncomprises a member selected from the group consisting of IO aidschemotherapeutic drugs, adrenal cortical steroid inhibitors, adrenalcorticosteroids, alcohol abuse reduction preparations, allergens,allergy relief products, amino acid preparations, analgesics,anesthetics, anorectal, antacids, antibacterials, antiseptics,antibiotics, anticholinergic drug inhibitors, anticoagulant antagonist,anticoagulants, antidepressants, antiduretus, antidose, antiglucomatous,antihistamines, antiinflammatory, antimetabolites, antineoplastics,antioxidants, antiparasites, antipyretus, antispasmodirs,anticholinergus, appetite suppressants, antiarthritics, asthma,biologicals, bone metabolism regulators, bowel evacuants, bronchialdilators, cardiovascular, cerebral metabolic enhancers, cholinesteraseinhibitors, cold drugs, contraceptives, convulsion medications,cortuosteroids, cough preparations, decongestants, dental preparations,dermatologicals, detoxifying agents, diabetes drugs, diagnostics,diarrhea medications, dietary supplements, diuretics, dopamine receptoragonist, duodenal ulcer adherent complex, electrolytes, enuresis,enzymes, ergot preparations, fertility agents, fibrinolytic agents,flatulence relief, fluoride preparations, foods, fungal agents,glactokinectics, galactorrhea inhibitors, gall stone dissolution agents,gastric acid secretion inhibitors, gastrointestinal motility factor,gonadotropin inhibitors, hair growth stimulants, hematinics,hemostatics, herpes treatment drugs, histamine receptor antagonists,hyperammonia reduction agents, hyperglycemia drugs, hypnotics,hypocalcemia management drugs, hypolipdimus, laxatives, menstrualagents, migraine drugs, minerals, motion sickness remedies, microlytics,muscle relaxant antagonist, muscle relaxants, mydriatics, narcoticantagonists, nasal drugs, nausea medications, neuroleptics, osteoporosisdrugs, oxytocics, parasympatholytic, parasympathommetics, Parkinsondrugs, prostagladins, protozal drugs, prurtis medications,psychostimulants, psychotic medications, respiratory stimulants,sedatives, sleep aids, smoking cessation aids, sympatholytics,sympathomimetics, throat lozenges drugs, thrombolytins, thyroid,preparations, tranquilizers, tremor preparations, tuberculosispreparations, uricosuric agents, urinary 10 tract agents, uterinecontractants, uterine relaxants, vaginal drugs, vertigo agents, viraltherapy, vitamins, and x-ray contrast agents. The dose unit amount of adrug in the delivery system is 1 mg to 750 mg. The generic drugs areknown in Phvsician's Desk References, 44th Edition, 1990, published byMedical Economics Company, Inc., Oradell, N.J.

DESCRIPTION OF METHODS OF PERFORMING THE INVENTION

Wall 12 of osmotic dosage form 10 can be formed in one technique usingthe air suspension procedure. This procedure consists in suspending andtumbling the compressed laminate in a current of air and wall formingcomposition until a wall is applied to the drug forming compartment. Theair suspensions procedure is well-suited for independently forming thewall. The air suspension procedure is described in U.S. Pat. No.2,799,241; J. Am. Pharm. Assoc., Vol. 48, pages 451 to 459, 1959; andibid. Vol. 49, pages 82 to 84, 1960. Osmotic dosage forms can also becoated with a wall-forming composition in a Wurster® air suspensioncoater, using acetone-water cosolvent, 90:10, wt:wt, using 2.5 to 4 wt %solids. The Aeromatic® air suspension coater using a methylenedichloride methanol cosolvent, 87:13, v:v, also can be used for applyingthe wall. Other wall forming techniques such as pan coating can be usedfor providing the dosage form. In the pan coating system, wall formingcompositions are deposited by successive spraying of the composition onthe bilayered compartment, accompanying by tumbling in a rotating pan. Apan coater is used to produce thicker walls. A larger volume of methanolcan be used in a cosolvent to produce a thinner wall. Finally, the wallcoated compartments are dried in a forced air oven at 30° C. to 50° C.for a week to free the dosage form of solvent. Generally, the wallsformed by these techniques have a thickness of 2 to 20 mils with apresently preferred thickness of 4 to 10 mils.

Dosage form IO of the invention is manufactured by standardmanufacturing techniques. For example, in one manufacturer thebeneficial drug and other ingredients comprising the first layer facingthe exit means are blended and pressed into a solid layer. The drug andother ingredients can be blended also with a solvent and mixed into asolid or semisolid formed by conventional methods such as ball-milling,calendering, stirring or rollmilling and then pressed into a preselectedshape. The layer possesses dimensions that correspond to the internaldimensions of the area the layer is to occupy in the dosage form and italso possesses dimensions corresponding to the second layer for forminga contacting arrangement therewith. Next, the osmopolymer, or hydrogellayer is placed in contact with the drug layer. The layering of the druglayer and the osmopolymer layer can be fabricated by conventionalpress-layering techniques. Finally, the two layer compartment formingmembers are surrounded and coated with an outer wall. A passageway islaser drilled through the wall to contact the drug layer, with thedosage form optically oriented automatically by the laser equipment forforming the passageway on the preselected surface.

In another manufacture, the dosage form is manufactured by the wetgranulation technique. In the wet granulation technique, the drug andthe ingredients comprising the first layer are blended using an organicor inorganic solvent, such as isopropyl alcohol-methylene dichloride80/20 v/v as the granulation fluid. Other granulating fluid such aswater or denatured alcohol 100% can be used for this purpose. Theingredients forming the first layer are individually passed through a 40mesh screen and then thoroughly blended in a mixer. Next, otheringredients comprising the first layer are dissolved in a portion of thegranulation fluid, such as the cosolvent described above. Then, thelatter prepared wet blend is slowly added to the drug blend withcontinual mixing in the blender. The granulating fluid is added until awet blend is produced, which wet mass then is forced through a 20 meshscreen onto oven trays. The blend is dried for 18 to 24 hours at 30° C.to 50° C. The dry granules are sized then with a 20 mesh screen. Next, alubricant is passed through an 80 mesh screen and added to the dryscreened granule blend. The granulation is put into milling jars andmixed on a jar mill for 10 to 15 minutes. The composition is pressedinto layers for example in a Manesty® press layer press. The secondlayer is pressed in a similar manner.

Another manufacturing process that can be used for providing thecompartment-forming composition comprises blending the powderedingredients in a fluid bed granulator. After the powdered ingredientsare dry blended in the granulator, a granulating fluid, for examplepoly(vinyl-pyrrolidone) in water, is sprayed onto the powders. Thecoated powders are then dried in a granulator. This process granulatesall the ingredients present therein while adding the granulating fluid.After the granules are dried, a lubricant such as stearic acid ormagnesium stearate is blended as above into the mixture. The granulesare pressed then in the manner described above.

The osmotic device of this invention is manufactured in anotherembodiment by mixing a drug with composition forming ingredients andpressing the composition into a solid lamina possessing dimensions thatcorrespond to the internal dimensions of the compartment space adjacentto a passageways. In another embodiment the drug and other firstcomposition forming ingredients and a solvent are mixed into a solid, ora semisolid, by conventional methods such as ballmilling, calendering,stirring or rollmilling, and then pressed into a preselected laminaforming shape. Next, a lamina of a composition comprising an osmopolymerand an optional osmagent are placed in contact with the laminacomprising the drug, and the two lamina comprising the laminate aresurrounded with a semipermeable wall. The lamination of the first drugcomposition and the second osmopolymer optional osmagent composition canbe accomplished by using a conventional two-layer tablet presstechnique. The wall can be applied by molding, spraying or dipping thepressed shapes into IO wall forming materials. Another and presentlypreferred technique that can be used for applying the wall is the airsuspension coating procedure. This procedure consists in suspending thetumbling the two layered laminate in current of air until the wallforming composition surrounds the laminate. The air suspension procedureis described in U.S. Pat. No. 2,799,241; J. Am. Pharm. Assoc., Vol. 48,pp 451-459 (1979); and, ibid, Vol. 49, pp 82-84 (1960). Other standardmanufacturing procedures are described in Modern Plastics Encyclopedia,Vol. 46, pp 62-70 (1969); and in Pharmaceutical Science, by Remington,14th Ed., pp 1626-1979, (1970), published by Mack Publishing Co.,Easton, PA.

Exemplary solvents suitable for manufacturing the wall, the laminatesand laminae include inert inorganic and organic solvents that do notadversely harm the materials and the final wall of the final laminatedwall. The solvents broadly include members selected from the groupconsisting of aqueous solvents, alcohols, ketones, esters, ethers,aliphatic hydrocarbons, halogenated solvents, cycloaliphatics,aromatics, heterocyclic solvents and mixtures thereof. Typical solventsinclude acetone, diacetone alcohol, methanol, ethanol, isopropylalcohol, butyl alcohol, methyl acetate, ethyl acetate, isopropylacetate, n-butyl acetate, methyl isobutyl ketone, methyl propyl ketone,n-hexane, n-heptane, ethylene glycol monoethyl ether, ethylene glycolmonethylacetate, methylene dichloride, ethylene dichloride, propylenedichloride, carbon chloroform, nitrethane, nitropropane,tetrachloroethane, ethyl ether, isopropyl ether, cyclohexane,cyclo-octane, toluene, naphtha, 1,4-dioxane, tetrahydrofuran, diglyme,aqueous and nonaqueous mixtures thereof, such as acetone and water,acetone and methanol, acetone and ethyl alcohol, methylene dichlorideand methanol, and ethylene dichloride and methanol.

DETAILED DISCLOSURE EXAMPLES OF THE INVENTION

The following examples are merely illustrative of the present inventionand they should not be considered as limiting the scope of the inventionin any way as these example and other equivalents thereof will becomeapparent to those versed in the art in the light of the presentdisclosure, the drawings and the accompanying claims.

EXAMPLE 1

A dosage form adapted, designed and shaped as an osmotic drug deliverydevice is manufactured as follows: first, all the ingredients arepre-sieved through a #40 mesh screen, and 50 g of bromocriptine mesylateis then blended with 40 g of maleic acid in a Hobert® blender for 15minutes. Then, add 200 g of hydroxypropylcellulose to the blend andcontinue mixing for 10 to 12 minutes. Next, blend 700 g of maltodextrinexhibiting a degree of polymerization of 11.1 and a molecular weight of1800 with the hydroxypropylcellulose, bromocriptine mesylate, maleicacid blend and blend all the ingredients for 20 minutes. Next, add 10 gof polyethylene glycol 30 castor oil, a surfactant, to 100 ml ofanhydrous ethyl alcohol and mix until dissolved; and then, slowly addthis alcohol solution to the mixing dry blend in the blender, to producea damp mass. Next, mix for 10 minutes and pass the damp mass through a20 mesh screen, to produce a damp granulation. Allow the granulation toair dry at ambient conditions over night. The dry mass then is passedthrough a 20 mesh screen to produce granules.

Next, 700 ml of distilled water is added to a stainless steel mixingvessel, its mixer started, followed by adding 63 g ofhydroxypropylcellulose to the water with mixing continuously to producea solution. The remaining dry ingredients are screened through a 40 meshscreen. Then, 550 g of sodium carboxymethylcellulose, 290 g of sodiumchloride, 77 g of hydroxypropylcellulose and optionally 20 g of ferricoxide are blended into a homogeneous blend. The just prepared blend isadded to a fluid bed granulator machine, and the above solution issprayed onto the screened blend. After all the granulating solution hasbeen sprayed onto the screened blend, the granulation is dried in thefluidizing air for about 10 minutes. The granulation is removed from thecolumn and passed through a 20 mesh screen. Next, 0.5 wt % of stearicacid and 0.2 wt % of silicon dioxide previously passed through an 80mesh screen is added to the granulation, and the ingredients are blendedfor 4 minutes to yield the second push composition.

The first composition and the second composition are arranged intobilayer cores by compressing 125 mg of the first composition and 85 mgof the second composition together under a force of about 2 tons. Thebilayer cores were coated with a coating solution comprising a binarysolvent of methylene chloride and methanol comprising cellulosetriacetate and polyethylene glycol. The bilayers were coated in anAeromatic®coater with 500 g of coating composition until a uniformsemipermeable coat is applied around the bilayers. The coated devicesare dried in an air oven at 30. C to 50° C. for up to 18 hours. Finally,a 25 mil orifice exit is drilled through the semipermeable wallconnecting the first composition with the exterior of the deliverydevice.

EXAMPLE 2

Following the procedure in Example 1, an osmotic dosage form is preparedcomprising: a first composition consisting of 5.00 wt % bromocriptinemesylate, 70 wt % maltodextrin of 1800 molecular weight, 20 wt %hydroxypropylcellulose of 60,000 molecular weight, 4 wt % maleic acidand 1 wt % polyethylene glycol 30 castor oil; a second compositioncomprising 55 wt % sodium carboxy- methylcellulose with a molecularweight of approximately 700,000 grams per mole, 29 wt % sodium chloride,14 wt % hydroxy- propylcellulose with a molecular weight of 60,000 gramsper mole and 2 wt % ferric oxide; a wall comprising 95 wt % celluloseacetate having a 39.8% acetyl content and a molecular weight ofapproximately 40,000 grams per mole, and 5 wt % polyethylene glycol; andor 30 mil exit passageway. The device exhibits a release rate in mg perhour as seen in drawing FIG. 5 and the cumulative amount released isseen in drawing FIG. 6.

EXAMPLE 3

Following the procedure of Examples 1 and 2, an osmotic dosage form ismanufactured wherein the first composition comprises an antiParkinsondrug selected from the group consisting of bromocriptine; bromocriptineand its therapeutically acceptable salts; bromocriptine mesylate; ergotderivatives including lisuride, pergolide, and mesulergine; levodopa;carbidopa; levodopa-carbidopa; amantadine; deprenyl; trihexyphenidyl;benztropine; biperiden; ethopropazine; procyclidine; dopamine agonists;monamine oxidase inhibitors, antichlolinergics including benztropinemesylate, trihexyphenidyl hydrochloride, procyclidine hydrochloride,biperiden hydrochloride, and ethopropazine.

EXAMPLE 4

An osmotic device is manufactured as follows: first, a drug compositionis prepared by adding 5 wt % deprenyl hydrochloride, 5 wt %hydroxypropylmethylcellulose, 30 wt % hydroxypropylcellulose, 60 wt %maltodextrin having a degree of polymerization of 7.4 and a molecularweight of 1200 to a blender and blending all of the ingredients forabout 8 minutes. Then, while the ingredients are mixing, 60 ml ofanhydrous ethanol is added slowly to the blender and the mixingcontinued for an additional 5 minutes. The wet granulation is passedthrough a 20 mesh screen, dried at room temperature for 16 hours andagain passed through a 20 mesh screen. Finally, 1 wt % magnesiumstearate pre-sifted through a 60 mesh screen is added to the granulationand all the ingredients mixed in a roller mill for 1 to 3 minutes.

Next, a second composition is prepared by mixing 30 wt % sodiumcarboxymethylcellulose, 18 wt % of polyethylene oxide with a molecularweight of approximately 5,000,000 grams per mole, 30 wt % of sorbitol,20 wt % of hydroxypropylcellulose and 1 wt % of ferric oxide to ablender and all the ingredients mixed in a blender to produce ahomogenous blend, which blend is passed through a 40 mesh screen. Next,50 ml of anhydrous ethanol is added slowly to the blending mixture andall the ingredients mixed for an additional 5 minutes. The freshlyprepared wet granulation is passed through a 30 mesh screen, allowed todry at room temperature for 16 hours, and again passed through a 30 meshscreen. The screened granulation is mixed with 1 wt % of stearic acid ina roller mill for 1 minute.

A two-layered press is used for forming a bilaminated core. First thecomposition comprising the deprenyl drug is added to the press andtampered, then, the second composition is added to the press, and thetwo laminates pressed under a pressure of 1.8 tons into a contactinglaminated arrangement.

Next, the laminate is surrounded with a semipermeable wall. The wallforming composition comprises 97 wt % cellulose acetate having an acetylcontent of 39.8% and 3 wt % polyethylene glycol having a molecularweight of 400 grams per mole. The wall-forming composition is dissolvedin acetone-water (95:5 wt:wt) cosolvent to make a 4% solids solution.The wall-forming composition is sprayed onto and around the bilaminatein an Aeromatic Air® Suspension Coater.

Finally, the wall coated bilaminates are dried for 24 hours at roomtemperature. Then, a 25 mil (0.635 mm) exit orifice is laser drilled onthe drug side of the osmotic device. The residual solvent is removed bydrying the osmotic device for 48 hours at 50° C. and 50% relativehumidity. The osmotic devices are then dried for 1 hour at 50° C. toremove any excess moisture.

EXAMPLE 5

An osmotic dosage form is manufactured as follows: first, ananti-Parkinson drug pair comprising bromocriptine and deprenyl is madeby adding 1700 ml of distilled water to a blender, to which is added 150g of maltodextrin polymer having a degree of polymerization of 11.1 anda molecular weight of 1,800 and the stirring continued to produce asolution. Next, 50 g of bromocriptine mesylate and 60 g of deprenylhydrochloride is added to the maltodextrin solution, and the mixingcontinued until all the ingredients comprising the first composition areblended with the solvent.

Next, 10 g of hydroxypropylcellulose having a molecular weight of100,000 and 15 g of polyvinyl pyrrolidone are blended to provide ahomogenous composition that is screened through a 40 mesh screen. Thescreened composition is added to a granulator column heated to 40° C.Then, the composition comprising the bromocriptine and the eldepryl andthe polyvinyl pyrrolidone is sprayed on the column to produce a wetgranulation. Next, the granulation is dried in the fluidizing air of thecolumn for about 10 minutes while maintaining the column at 30° C. Thegranulation is removed from the column and screened through a 20 meshscreen. Next, 0.5 g of magnesium stearate is added to the granulationaccompanied by 2 minutes of blending to yield the bidrug granulation.

Next, 700 ml of distilled water is added to a mixer, followed by 63 g ofhydroxypropylcellulose having a 70,000 molecular weight with continualmixing to yield a solution. Then, 550 g of sodium chloridecarboxymethylcellulose, 150 g of sodium chloride, 140 g of mannitol, and70 g of hydroxypropylcellulose having a 60,000 molecular weight, andoptionally 20 g of ferric oxide are blended into a homogenous blend, andthen screened through a 40 mesh screen. The screened blend is added tothe granulation solution in the granulator and it is sprayed onto theblend. Then, the granulation is dried in the fluidizing air for about 10minutes, removed from the column and screened through a 20 mesh screen.Then, 3 g of magnesium stearate and 5 g of silicon dioxide are added tothe granulation, the ingredients blended for 6 minutes and screenedthrough a 80 mesh screen to yield the expandable composition.

The first composition and the second composition are arranged andpressed into bilayer cores by compressing 155 mg of the firstcomposition and 95 mg of the second composition together under a forceof 1.8 tons. The bilayers are coated with a coating solution comprisingmethylene chloride-methanol, cellulose triacetate and polyethyleneglycol. The bilayers are coated in an air suspension coater with 500 gof the coating composition. The coated devices are dried in an air ovenfor 18 hours at 50° C. A 30 ml orifice is drilled through thesemipermeable wall for connecting the drug composition with the exteriorof the device.

EXAMPLE 6

A novel dosage form provided by the invention is manufactured asfollows: first, 70 wt % of mannitol is put through a 40 mesh screen andthen sieved through a 60 mesh screen, all the mannitol that went throughthe 60 mesh screen is used for preparing the dosage form. Next, 5 wt %eldepryl hydrochloride and 10 wt % carbidopalevodopa, 5 wt %microcrystalline cellulose, and 8 wt % of a maltodextrin comprising amolecular weight of 20,000 and a degree of polymerization of 123independently are screened through a 40 mesh screen, and the screenedingredients mixed in a blender with the mannitol for about 20 minutes toproduce a homogenous blend. Next, 1 wt % silicon dioxide is screenedthrough an 80 mesh screen, and then 1 wt % magnesium is screened thoughan 80 mesh screen. The screened silicon dioxide and the screenedmagnesium stearate are added to the blend comprising the mannitol,eldepryl, carbidopa-levodopa, microcrystalline cellulose, and themaltodextrin polymer and blended for 5 minutes.

Next, 80 wt % of a copolymer of N-vinyl lactam and N-vinyl pyrrolidone,13 wt % of sodium chloride, and 5 wt % of hydroxypropylmethylcelluloseare wet granulated using ethyl alcohol as the granulating fluid. The wetgranulation is screened through a 16 mesh screen and dried on trays at50° C. in an oven overnight. The dried granulation is screened through a16 mesh screen. Then a mixed lubricant comprising 1 wt % magnesiumstearate and 1 wt % stearic acid is screened through a 80 mesh screenand added to the dried granulation. Finally, all the ingredients areblended for 5 minutes to yield a homogenous blend.

A dosage form comprising a first drug layer, and a hydrophilic layer isprepared in a Carver® press using a 1/4 inch, standard concave die.First, 86 mg of the composition comprising the drug layer is placed inthe die and pinched to compress the granulation. The, the second-forminglayer comprising the hydrophilic polymer is placed on top of the firstlayer and compressed with 2.5 tons of force.

The two-layered laminate is surround with a wall in an Aeromatic®Coater. The wall-forming composition comprised 51 g of cellulose acetatehaving an acetyl content of 43.5%, 9 g of hydroxypropylcellulose, and acosolvent comprising 1,170 ml of methylene chloride and 490 ml ofmethanol. During the wall-forming process, 960 ml of wall-formingsolution are used to apply a 12.3 mg wall on each two-layered dosageform. The dosage forms are dried in an oven overnight at 50° C. to yielda final dry wall of 10.4 mg per dosage form. A single 15 mil, (0.381 mm)passageway is drilled through the wall connecting the exterior of thedosage form with the first layer. The first layer is selected by visualexamination. In an automatic laser drilling technique, the drug layer isselected by the photo examination apparatus of the laser. The dosageform delivers 98.6% of its drugs in 24 hours.

EXAMPLE 7

The procedure of example 1 is repeated with the manufacturing steps aspreviously described, except that sodium chloride is replace by anosmotically effective solute selected from the group consisting ofpotassium chloride, magnesium chloride, d-mannitol and fructose.

EXAMPLE 8

An exterior, quick-releasing lamina comprising the drug pairbromocriptine mesylate and deprenyl hydrochloride and at least onequick-releasing member selected from the group consisting ofhydroxypropylcellulose and hydroxypropylmethylcellulose are added to afluid bed granulator and the materials blended in a moving current ofair. Then, a granulating fluid is sprayed onto the fluidizing powersuntil the powders are wet granulated. Next, the fluidizing process iscontinued until the granulation is dry. The immediate release lamina iscompressed or air sprayed around the external surface of the deliverydevice as prepared in the previous examples to yield an immediaterelease coat comprising the bromocriptine and the deprenyl.

DISCLOSURE OF METHOD OF PERFORMING THE INVENTION

An embodiment of the invention pertains to a method for delivering abeneficial drug at a controlled rate orally to a warm-blooded animal inneed of drug therapy, which method comprises the steps of: (A) admittinginto the warm-blooded animal a dosage form comprising: (1) a wallsurrounding a compartment, the wall comprising at least in part asemipermeable polymeric composition permeable to the passage of fluidand substantially impermeable to the passage of drug; (2) a layer in thecompartment comprising a formulation comprising a dosage unit amount ofa drug for performing a therapeutic program and a maltodextrin; (3) alayer in the compartment comprising an osmotic formulation for imbibing,and absorbing fluid for expanding in size for pushing the drugmaltodextrin formulation from the dosage form; and, (4) at least one IOpassageway in the wall for releasing the drug; (B) imbibing fluidthrough the semipermeable part of the wall at a rate determined by thepermeability of the semipermeable wall and the osmotic pressure gradientacross the semipermeable wall causing the osmotic layer to expand andswell; and (C) delivering the beneficial drug from the dosage formthrough the exit passageway to the warm-blooded animal over a prolongedperiod of time. The method of the invention can be used foradministering bromocriptine as a prolactin inhibitor.

Dosage form 10 of this invention, and as seen in the above drawingfigures, can be used in a method for administering a drug by the oralroute, and in another method the dosage form can be sized and shaped foradministering a drug by the sublingual and buccal routes. The sublingualand buccal routes can be used for quicker therapy and they can be usedwhen a smaller dose of drug is needed for therapy. The latter routes canbe used as a by-pass of the first pass of hepatic metabolism of thedrug. The sublingual or buccal routes can be used for administering adrug such as eldepryl, levodopa-carbidopa and the like, and foradministering more than one drug such as eldepryl as an adjunct in themanagement of Parkinsonian patients being treated withlevodopa-carbidopa, and the like.

In summary, it will appreciated that the present invention contributesto the art an unobvious dosage form that possesses practical utility,can administer a drug at a dose metered release rate per unit time.While the invention has been described and pointed out in detail withreference to operative embodiments thereof, it will be understood thatthose skilled in the art that various changes, modifications,substitutions and omissions can be made without departing from thespirit of the invention. It is intended, therefore, that the inventionembraces those equivalents within the scope of the claims which follow.

We claim:
 1. An improvement in a dosage form for delivering a drug to ananimal, wherein the dosage form comprises:(a) a wall comprising acomposition permeable at least in part to the passage of fluid, whichwall surrounds; (b) a compartment; (c) at least one exit passageway inthe wall that connects the exterior of the dosage form with thecomposition; (d) a composition in the compartment comprising a hydrogelthat in the presence of fluid in the compartment expands and occupiesspace in the compartment; and, (e) a composition in the compartmentcomprising a and an osmotically effective solute, wherein theimprovement comprises a maltodextrin in the composition that iscompatible with the drug, aids in delivering the drug through thepassageway from the compartment and comprises a 500 to 1,000,000molecular weight and a degree of polymerization of 3 to 6,140.
 2. Thedosage form for delivering a drug according to claim 1, wherein the drugis a member selected from the group consisting of bromocriptine and itstherapeutically acceptable salts.
 3. The dosage form for delivering adrug according to claim 1, wherein the drug is a member selected fromthe group consisting of eldepryl and its therapeutically active salts.4. The dosage form for drug according to claim 1, wherein the drug is amember selected from the group consisting of lisuride, pergolide,mesulergine, levodopa, carbidopa, levodopa-carbidopa, amantadine,trihexyphenidyl, benztropine, biperiden, ethopropazine, procyclidine,benztropine mesylate, trihexyphenidyl hydrochloride, procyclidinehydrochloride, and biperiden hydrochloride.
 5. The dosage form for drugaccording to claim 1, wherein the drug is present in the composition asa drug pair, said pair comprising a member selected from the groupconsisting of bromocriptine, lisuride, pergolide, mesulergine, levodopa,carbidopa, levodopa-carbidopa, amantadine, deprenyl, trihexyphenidyl,benztropine, biperiden, ethopropazine, and procyclidine, and a differentmember selected from the group consisting of bromocriptine, lisuride,pergolide, mesulergine, levodopa, carbidopa, levodopacarbidopa,amantadine, deprenyl trihexyphenidyl, benztropine, biperiden,ethopropazine, and procyclidine.
 6. An improvement in a method of drugtherapy, wherein the method comprises:(A) admitting into a patient adosage form, which dosage form comprises:(1) a wall comprising acomposition that is permeable to the passage of fluid, which wallsurrounds; (2) a compartment; (3) a composition in the compartmentcomprising a non-toxic hydrogel that imbibes fluid and expands in thepresence of the imbibed fluid; (4) a passageway in the wall connectingthe exterior of the dosage form with the compartment; (5) a compositionin the compartment comprising a drug and wherein the improvementcomprises a maltodextrin in the composition that is compatible with thedrug for providing substantially complete delivery of the drug from thedosage form; (B) imbibing fluid into the compartment for the hydrogel toabsorb and expand thereby pushing the drug through the passageway; and(c) administering the drug to the patient in need of the drug.
 7. Animprovement in a method of drug therapy according to claim 6, whereinthe drug is bromocriptine administered as a prolactin inhibitor.